Process for producing an optically active 1,5-disubstituted-2,4-O-isopropylidene-2,4-dihydroxypentane

ABSTRACT

A novel optically active erythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substituted pentane expressed by the formula ##STR1## wherein R 1  represents a halogen atom or cyano group and R 2  represents an alkyl group of 1 to 6 carbon atoms, and a process for producing the above compound are provided, the compound being preferably usable as an intermediate for preparing a HMG-CoA reductase inhibitor and the process being practiced under mild conditions and with a high yield.

This application is a divisional of application Ser. No. 08/070,985,filed Jun. 4, 1993, now U.S. Pat. No. 5,329,018.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method of producing a novel opticallyactivate substance, preferably usable as an intermediate for preparingHMG-CoA reductase inhibitor, known as a remedy for high cholesterolblood disease.

2. Description of the Related Art

The HMG-CoA reductase inhibitor has been noted as a remedy for highcholesterol blood disease, and a number of its homologues have beensynthesized and active research of its pharmaceutical activity has beencarried out. As one area of research, a pyrrole derivative of thefollowing formula (7) has been disclosed in U.S. Pat. No. 4,681,893(Bruce D. Roth et al): ##STR2##

Further, an effective process for producing the compound of the formula(7) has been disclosed in U.S. Pat. No. 5,003,080 (Donald E. Butler etal). The literature of the prior art shows that when the followingcompounds of the formulas (8) and (9) are treated with 10% hydrochloricacid, the compound of the formula (7) can be easily prepared: ##STR3##

Further, it is also shown that the other preparation fragment (9) isprepared by catalytically reducing the following nitrile compound (10)at 0° to 70° C.: ##STR4##

However, the process for producing the nitrile compound (10), disclosedin the above literature of the prior art is commercially inferior.Namely, the disclosed process for producing the nitrile compound (10)consists of the following steps:

Firstly, an alkyllithium, iodine and CO₂ in this order are reacted with1,6-heptadiene-4-ol (11) to generate an iodide (12) in the reactionsystem, followed by treating it with an alkali or alkaline earthhydroxide or carbonate to prepare an epoxide (13). ##STR5##

An alkali metal cyanide is reacted with the epoxide to open the oxiranering, followed by ketalization to obtain (14), oxidizing it with ozoneat -20° to -78° C. to obtain an aldehyde (15), further oxidizing it withJones reagent to obtain a carboxylic acid (16), and esterifying it withan alkyl halide in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene(DBU) to obtain (17). ##STR6##

However, the above processes have the following commercialdisadvantages:

1. In the preparation of (12), it is necessary to use an alkyllithiumwhich is difficult to deal with.

2. In the preparation of (15), it is necessary to carry out ozoneoxidation at low temperatures (-20° to -78 ° C.).

3. In the preparation of (16), it is necessary to use Jones reagentcontaining harmful chromic acid.

Furthermore, according to this preparation route, while it is possibleto separately prepare an erythro-form substance and a threo-formsubstance, it is impossible to prepare an optically active substance.Thus, the final product prepared through the preparation route is aracemic substance. A pyrrole derivative having a physiological activityas HMG-CoA reductase inhibitor is only 2R-transform substance expressedby the formula (7), and optical isomers have no activity.

The above U.S. Pat. No. 5,003,080 also discloses preparation of anoptically active substance. Namely, the above optically active nitrilecompound (10) is prepared through the following route:

A carboxylic acid (19) derived from isoascorbic acid (18) according to aknown method has one more carbon atom increased, usingcarbonyldiimidazole and a half ester of malonic acid, to prepare (20),followed by removing the protective group to obtain an alcohol (21).

This alcohol is stereoselectively reduced with triethylborane ormethoxydiethylborane and then with sodium borohydride, at -78° to -110°C., preferably -100° C., to obtain a diol (22), followed by protectingthe hydroxyl groups with acetonide to obtain the above nitrile compound(10). ##STR7##

However, the above process cannot be regarded as a commerciallyadvantageous process, since conversion of the isoascorbic acid (18) intothe carboxylic acid (19) requires a number of steps and reduction of thealcohol (21) requires an extremely low temperature (because nostereoselectivity is exhibited at high temperatures). Thus, a noveloptically active compound equivalent to optically active nitrilecompound (10) or easily convertible into (10), and a process forproducing a novel optically active compound easily convertible into (10)under mild reaction conditions and commercially advantageously, havebeen required.

The present inventors have made extensive research in order to solve theabove-mentioned problems, and as a result, have found a novel and usefuloptically active compound, i.e. an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substitutedpentane (1) of the present invention, equivalent to or easily convertedinto an optically active nitrile compound (10) as a raw material forpreparing a pyrrole derivative (7) which is one of HMG-CoA reductaseinhibitors, and a suitable and simple process for producing the compoundof the present invention (1); thus the present invention has beencompleted.

As apparent from the foregoing, the object of the present invention isto provide the above-mentioned novel compound and a process forproducing the same.

SUMMARY OF THE INVENTION

The present invention has the following constitutions:

An optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substitutedpentane expressed by the formula ##STR8## wherein R¹ represents ahalogen atom or cyano group and R² represents an alkyl group of 1 to 6carbon atoms. 2. A process for producing an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane,which process comprises reacting an ester withmeso-1,2,4,5-pentanetetraol expressed by the formula ##STR9## in thepresence of a lipase to prepare ameso-1,5-alkanoyloxy-2,4-dihydroxypentane expressed by the formula##STR10## wherein R ³ represents an alkyl group of 1 to 10 carbon atoms;ketalizing the compound (3) to prepare ameso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentaneexpressed by the formula ##STR11## dealkanolizing the compound (4) toprepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed bythe formula ##STR12## reacting an ester with (5) in the presence of alipase to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR13## wherein R² represents an alkyl group of 1 to 6carbon atoms, and halogenating it, to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneexpressed by the formula ##STR14## wherein R¹ represents a halogen atomand R² represents an alkyl group of 1 to 6 carbon atoms.

3. A process for producing an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane,which process comprises reacting an ester with,meso-1,2,4,5-pentanetetraol expressed by the formula ##STR15## in thepresence of a lipase to prepare ameso-1,5-alkanoyloxy-2,4-dihydroxypentane expressed by the formula##STR16## wherein R³ represents an alkyl group of 1 to 10 carbon atoms;ketalizing the compound (3) to prepare ameso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentaneexpressed by the formula ##STR17## dealkanolizing the compound (4) toprepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed bythe formula ##STR18## reacting an ester with (5) in the presence of alipase to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR19## wherein R² represents an alkyl group of 1 to 10carbon atoms, halogenating it, to prepare an optically activealkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneexpressed by the formula ##STR20## wherein R¹ represents a halogen atomand R² represents an alkyl group of 1 to 6 carbon atoms, and cyanizingit, to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentaneexpressed by the formula ##STR21## wherein R¹ represents a cyano groupand R² represents an alkyl group of 1 to 6 carbon atoms.

4. A process for producing an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR22## wherein R² represents an alkyl group of 1 to 6carbon atoms, which process comprises reacting an ester withmeso-2,4-O-isopropylidene-1,2,4,5-pentanetetraol expressed by theformula ##STR23## in the presence of a lipase.

5. A process for producing a meso-1,5-dialkanoyloxy-2,4-dihydroxypentaneexpressed by the formula ##STR24## wherein R³ represents an alkyl groupof 1 to 10 carbon atoms, which process comprises reacting an ester withmeso-1,2,4,5-pentanetetraol expressed by the formula ##STR25## in thepresence of a lipase.

6. A process for producing an optically activeerythro-3,5-O-isopropylidene; 3,5,6-trihydroxy-hexanoate, which processcomprises reacting an ester with meso-1,2,4,5-pentanetetraol expressedby the formula ##STR26## in the presence of a lipase to prepare ameso-1,5-alkanoyloxy-2,4-dihydroxypentane expressed by the formula##STR27## wherein R³ represents an alkyl group of 1 to 10 carbon atoms;ketalizing the compound (3) to prepare ameso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentaneexpressed by the formula ##STR28## dealkanolizing the compound (4) toprepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed bythe formula ##STR29## reacting an ester with (5) in the presence of alipase to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR30## wherein R² represents an alkyl group of 1 to 6carbon atoms, halogenating it, to prepare an optically activealkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneexpressed by the formula ##STR31## wherein R¹ represents a halogen atomand R² represents an alkyl group of 1 to 6 carbon atoms, and cyanizingit, to prepare an optically activateerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentaneexpressed by the formula ##STR32## wherein R¹ represents a cyano groupand R² represents an alkyl group of 1 to 6 carbon atoms, and convertingthe cyano group into an alkoxycarbonyl group, to prepare an opticallyactive erythro-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate expressedby the formula ##STR33## wherein R⁴ represents an alkyl group of 1 to 6carbon atoms.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

A compound of the formula (1) of the present invention wherein R¹represents a cyano group has an alkanoyloxy group at the 1-position anda cyano group at the 5-position in the molecule. The cyano group at the5-position is equivalent to a carboxyl group in the aspect oforganosynthetic chemistry; hence if required, the cyano group can beeasily converted into a carboxyl group according to a conventionalorganochemical method. Further, the alkanoyloxy group can be easilyconverted into a hydroxyl group under mild conditions i.e. by treatingit with calcium carbonate, sodium carbonate or the like in an alcohol,and this hydroxyl group can be further converted into a cyano groupunder similar mild conditions as shown in the examples, the fifth stepand the sixth step mentioned below.

In short, the compound of the formula (1) of the present invention canbe regarded as equivalent to the optically active nitrile compound (10)which is a raw material for preparing the pyrrole derivative (7) as oneof the HMG-CoA reductase inhibitors, or regarded as a compound which canbe easily converted into (10). Further, as shown in the Examples, it ispossible to prepare (1) which is stereochemically a (2S,4S) substance,in a superior optical purity, according to the method of the presentinvention, and this is a preferable steric substance as a raw materialfor preparing the pyrrole derivative (7) having a physiologicalactivity.

Among the compounds of formula (1) of the present invention, a compoundof formula (1) wherein R¹ represents a halogen atom is prepared via fivesteps starting from meso-1,2,4,5-pentanetetraol (2), while a compound ofthe formula (1) wherein R¹ represents a cyano group is prepared via sixsteps.

(First step) Preparation of meso-1,5-dialkanoyloxy-2,4-dihydroxypentane(3)

The first reaction step is carried out by agitating a mixture ofmeso-1,2,4,5-pentanetetraol (2), a lipase and an ester to subject onlyhydroxyl groups at the 1 and 5 positions to ester exchange. In thiscase, the ester exchange reaction advances only at the primary hydroxylgroups and selective esterification can be effected only at the 1, 5positions. As to the usable lipase, any kinds are usable as far as theycan selectively esterify only the primary hydroxyl groups.

As to the lipase usable in this case, commercially available ones may besufficient, for example, Lipase AP (origin: Aspergillus nigar, made byAmano Pharmaceutical Co. Ltd.), Lipase M (origin: Mucor javanicus, madeby Amano Pharmaceutical Co. Ltd.), Lipase P (origin: Pseudomonasspecies, made by Amano Pharmaceutical Co.,Ltd.), Lipase PS (origin:Pseudomonas species, made by Amano Pharmaceutical Co. Ltd.),Lipase CES(origin: Pseudomonas species, made by Amano Pharmaceutical Co. Ltd.),Lipase CE (origin: Humicola lanuginosa, made by Amano Seiyaku Co.,Ltd.), Lipase II (origin: porcin pancreas, made by Cygma Co., Ltd.),Lipase VIII (origin: Geotrichumu candidom, made by Cigma Co., Ltd.),Lipase X (origin: Rhizopus delemar, made by Cigma Co., Ltd.), Lipase(origin: Chromobacterium viscosum, made by Toyo Jozo Co., Ltd.),Palatase A (origin: Aspergillus nigar, made by Novo Industry, Co.,Ltd.), Lipase (origin: Rhizopus nivenus, supplied by Nagase Sangyo Co.,Ltd.) and lipase B (origin: Pseudomonas fragi, made by Sapporo Beer Co.,Ltd.).

The quantity of the ester used may be 2 to 3 molar equivalents to (2).However, since the reaction rate of the ester exchange reaction at theprimary hydroxyl group is far higher than that at the secondary hydroxylgroup, a large excess quantity of the ester may be used.

Examples of the ester used are alkyl carboxylates such as alkylacetates, alkyl propionates, alkyl butanoates, alkyl pentanoates, alkylhexanoates, alkyl heptanoates, vinyl esters such as vinyl acetate, vinylpropionate, vinyl butanoate, vinyl pentanoate, vinyl hexanoate, vinylheptanoate, vinyl laurate, etc., triglycerides such as triacetin,tributyrin, tricaproin, etc.

In this case, since the steric selectivity is not influenced by thealkyl chain length, it is also possible to use any chain length ester. Areaction-solvent is not always required, but since the solubility of (2)in the ester is low, it is preferred to use a co-solvent such asdimethylformamide at an appropriate time.

Withdrawal of the objective substance (3) from the reaction system aftercompletion of the reaction can he easily carried out as follows:

Namely, when the lipase in a suspension state is filtered off and thefiltrate is concentrated, a raw substance (3) is obtained. This materialis usable for the subsequent reaction without purification. Further, thelipase filtered off can he reused as it is. For the reactiontemperature, room temperature is sufficient. The reaction time is 1 to50 hours.

(Second step) Preparation ofmeso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentane (4)

The second reaction step is carried out by reacting acetone or2,2-dimethoxypropane with meso-1,5-dialkanoyloxy-2,4-dihydroxypentane(3) in the presence of an acid catalyst. As the acid catalyst, mineralacids such as sulfuric acid, hydrochloric acid, etc., sulfonic acidssuch as p-toluenesulfonic acid, camphor-sulfonic acid, etc., and anacidic ion exchange resin are preferably used. As the reactiontemperature, those temperature in the vicinity of room temperature arepreferred. The reaction can be carried out in the absence of solvent,but if the solubility of (3) is low, it is preferred to carry out thereaction by adding dimethylformamide at an appropriate time.

(Third step) Preparation ofmeso-2,4-isopropylidene-1,2,4,5-pentanetetraol (5)

The third reaction step is carried out by deacetylatingmeso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentane (4)under a neutral or basic condition. For example, the reaction is carriedout by reacting therewith sodium carbonate, potassium carbonate, calciumcarbonate, barium carbonate, potassium hydroxide, sodium hydroxide,calcium hydroxide, barium hydroxide or the like in a polar solvent suchas methanol, ethanol, isopropanol, water or the like.

Further, it is also possible to dealkanoylize it in a reducing manner,by reacting a reducing agent such as lithium aluminum hydride, lithiumboron hydride, sodium boron hydride or the like in a solvent such asdiethyl ether, tetrahydrofuran or the like.

(Fourth step) Preparation of optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6)

The fourth reaction step is carried out by agitating a mixture ofmeso-2,4-O-isopropylidene-1,2,4,5-pentanetetraol (5), a lipase and anester to subject only one of hydroxyl groups at the 1 and 5 positions toester exchange. In this case, the ester exchange reaction advancesstereoselectively to obtain the optically active (6). As to the lipaseused, any kinds may be used as far as only one of the hydroxyl groups at1 and 5 positions can be stereoselectively esterified.

For the lipase used in this case, commercially available lipases aresufficient. Examples thereof have been mentioned in the above firststep. Among these, lipases of Pseudomonas genus origin are particularlypreferred.

The quantity of the ester used may be 1 to 2 molar equivalents basedupon (5), but since the stereoselectivity of the ester exchange reactionis high, the ester may be used in a large excess quantity. As the esterused, alkyl carboxylates such as alkyl acetates, alkyl propionates,alkyl butanoates, alkyl pentanoates, alkyl hexanoates, alkylheptanoates, vinyl esters such as vinyl acetate, vinyl propionate, vinylbutanoate, vinyl pentanoate, vinyl hexanoate, vinyl heptanoate,triglycerides such as triacetin, tributyrin, tricaproin, are preferablyused.

Since the stereoselectivity is not influenced by the alkyl chain length,it is also possible to use any chain length ester. The reaction solventis not always required, but when the solubility of (5) in the ester islow, it is preferred to use a co-solvent such as dimethylformamide at anappropriate time. Withdrawal of the objective substance (6) from thereaction system after completion of the reaction can be easily carriedout as follows:

Namely, by filtering off the lipase in a suspended state and thenconcentrating the filtrate, the objective compound (6) is obtained.Further, the lipase filtered off can be reused as it is. For thereaction temperature, room temperature may be sufficient. The reactiontime is 0.5 to 50 hours.

(Fifth step) Preparation of optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane(a compound of the formula (1) wherein R¹ represents a halogen atom)

The fifth reaction step is carried out by halogenating the opticallyactive erythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6)in a neutral or basic condition. For example, it is possible to preparea chloride (a compound of the formula (1) wherein R¹ represents achlorine atom) by heating (6) under reflux in carbon tetrachloride inthe presence of triphenylphosphine or treating (6) with N-chlorosuccinicacid imide in dichloromethane in the presence of triphenylphosphine.

Further, it is possible to prepare a bromide (a compound of the formula(1) wherein R¹ represents a bromine atom) by reacting one equivalent ormore of N-bromosuccinic acid imide or 2 to 3 equivalents of carbontetrabromide with (6) in dichloromethane in the presence of oneequivalent of triphenylphosphine. Further, it is possible to prepare aniodide (a compound of the formula (1) wherein R¹ represents an iodineatom), by reacting triphenylphosphine and iodine with (6) in thepresence of imidazole. The iodide can also be prepared by treating thechloride or bromide with sodium iodide in acetone.

(Sixth step) Preparation of an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane(a compound of the formula (1) wherein R¹ represents a cyano group)

The sixth reaction sixth step is carried out by reacting sodium cyanide,potassium cyanide or copper cyanide with an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane(a compound of the formula (1) wherein R¹ represents a halogen atom) indimethylformamide or dimethylsulfoxide.

In the case where the optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneis an iodide, the reaction proceeds at room temperature, but in the casewhere it is a chloride or a bromide, heating is required for thereaction.

As to the preparation of meso-1,2,4,5-pentanetetraol (2) as the startingraw material, a preparation method using adonitol as the raw material(Zhuo-Feng XIE et al, Chem. Pharm. Bull., 37, (6), 1650 (1989)), and apreparation method using 1,2-O-isopropylidene-1,2,4-butanetriol as theraw material (Johann Mulzer et al, Liebig's Ann. Chem., 947 (1991)) havebeen known; hence (2) can be prepared according to such methods.

As to the preparation of optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6), aseparate preparation method has been reported by Zhuo-Feng XIE et al(Zhuo-Feng XIE et al, Chem. Pharm. Bull., 37 (6), 1650 (1989)). (6) isprepared by selective protection of hydroxyl groups at the 1 and 5positions of meso-1,2,4,5-pentanetetraol and protection of the 2 and 4positions with acetonide and succeeding asymmetric hydrolysis of theresulting diacetate with a lipase. However, as to the selectivity of theselective protection of hydroxyl groups at the 1 and 5 positions with anacetyl group using acetic anhydride, the yield is as low as 61%.Whereas, the yield of the compound having hydroxyl groups at 1 and 5positions protected with the alkanoyloxy group in the present inventionwas 75%.

Further, the optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentatriol obtained bythe asymmetric hydrolysis with a lipase has a stereochemical structureof (2R,4R), that is, an antipode to the compound sought; hence the abovemethod is not a commercially useful method.

Further, it is necessary to carry out assymetric hydrolysis with alipase in water, but since the substrate is not water-soluble, a largequantity of reaction solvent is required. Further, recovery of lipasefrom water and its reuse are impossible. (Effectiveness of theInvention)

The novel compound of the present invention, optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substitutedpentane (1), is an equivalent compound to an optically active nitrilecompound (10) which is a raw material for preparing a pyrrole derivative(7) as one of HMG-CoA reductase inhibitors, or a compound which can beeasily converted into (10).

Further, the novel compound of the present invention, optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-substitutedpentane (1) can be preferably used not only for the above opticallyactive nitrile compound (10) which is a raw material for preparing apyrrole derivative (7) as one of HMG-CoA reductase inhibitors, but alsofor a raw material for preparing physiologically active compounds asmentioned below. Examples thereof are as follows:

The novel compound of the present invention, optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane(a compound of the formula (1) wherein R¹ represents cyano group) iseasily lactonized by hydrolysis of the cyano group, followed by acidtreatment, to afford a lactone (22). ##STR34##

This product can afford the lactone site of Compactin (Formula 23) knownas one of HMG-CoA reductase inhibitors (A. G. Brown et al, J. Chem. Soc.Perkin Trans. I, 1165 (1976)) or that of mevinolin (Formula 24)similarly known thereas (A. W. Alberts et al, Proc. Natn. Acad. Sci.U.S.A. 77, 3957 (1980)). ##STR35##

Further, the novel compound of the present invention, optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane(a compound of the formula (1) wherein R¹ represents cyano group), isalso useful as a raw material for preparing a pyridine derivative(Formula 25) (Eur. Pat. Appl., EP 356778) which is also an HMG-CoAreductase inhibitor. ##STR36##

Namely, an aldehyde (formula (26)) is prepared by removal of theprotective alkanoyloxyl group from the 1-position and oxidation,followed by introduction of a pyridine core, hydrolysis, removal ofacetonide and conversion of the ester site into a metal salt to prepare(25). ##STR37##

Further, in the present invention, such useful novel optically activecompounds can be prepared in a simple manner. Next, the effectiveness ofthe procedure of the present invention will be enumerated.

1 The esterification at the first step has a high region-selectivity;hence only the primary hydroxyl group can be esterified withoutemploying any particular condition.

2 The esterification with a lipase at the first and third steps can becarried out in an organic solvent; hence in spite of an enzymaticreaction, the reaction can be carried out in a high substrateconcentration.

3 The esterification with a lipase at the first and third steps can becarried out in an organic solvent; hence the recovery of the lipaseafter used and its reuse are easy.

4 The esterification with a lipase at the fourth step has a highstereoselectivity; hence it is possible to obtain an optically purecompound by a once enzymatic reaction.

5 The reaction conditions at the respective steps are very mild. Thereactions at any steps except for the sixth step are all carried out atroom temperature.

6 The yields at the respective steps are high (1st. step: 75%, 2nd.step: 63%, 3rd. step: quantitative, 4th step: 70%, 5th step: 77%, 6thstep: 55% and the total yield: 14%).

EXAMPLES

The present invention will be described in more detail by way ofrepresentative examples.

EXAMPLE 1

(First step)

Preparation of meso-1,5-diacetoxy-2,4-dihydroxy-pentane (3)

A mixture of meso-1,2,4,5-pentanetetraol (2) (25.7 g, 0.19 mol),LipasePS (made by Amano Pharmaceutical Co., Ltd.) (9 g), vinyl acetate (48.7g,0.57 mol) and dimethylformamide (DMF) (40 ml) was agitated at roomtemperature for 28 hours.

The Lipase PS was filtered off, followed by washing the filtrationresidue with ethyl acetate (50 ml), combining the filtrate with ethylacetate used for the washing, and concentrating the mixture underreduced pressure to obtain as a residue an, orange colored, oilymeso-1,5-diacetoxy-2,4-dihydroxypentane (3) (25.2 g, yield: 75%). Thisproduct was used as a raw material for the second step withoutpurification.

(Second step )

Preparation ofmeso-1,5-diacetoxy-2,4-O-isopropylidene-2,4-dihydroxypentane (4)

p-Toluenesulfonic acid monohydrate (2.5 g, 0.013 mol) was added to amixture of meso-1,5-diacetoxy-2,4-dihydroxypentane (3) (25.2 g, 0.14mol) obtained at the first step, 2,2-dimethoxypropane (400 ml) and DMF(200 ml), under ice cooling, followed by agitating the resulting mixtureat room temperature for 22 hours.

Sodium hydrogen carbonate (20 g) was added under ice cooling, followedby agitating the mixture for one hour, adding a saturated aqueoussolution of sodium hydrogen carbonate (300 ml), extracting the mixturewith ethyl acetate (300 ml), twice washing the organic layer with water(200 ml) and drying over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure, followed bysubjecting the residue to silica gel column chromatography (eluent:toluene-ethyl acetate (8:1), Rf value: 2.0), to obtain a rawmeso-1,5-diacetoxy-2,4-O-isopropylidene-2,4-dihydroxypentane (4) in theform of a yellow oily substance.

This substance was recrystallized from n-heptane(100ml) to obtainmeso-1,5-diacetoxy-2,4-O-isopropylidene-2,4-dihydroxypentane (4) (22.8g, yield: 63%) in the form of colorless needles).

M. P.: 50.7°-53.5° C.

¹ H-NMR (90 MHz, CDCl₃) δ(ppm): 1.36-1.68 (3H, m), 1.43 (3H, s), 1.46(3H, s), 2.09 (6H, s), 4.01-4.21 (6H, m) ¹³ C-NMR (90 MHz, CDCl₃)δ(ppm): 19.5, 20.5, 29.0, 29.5, 67.5, 99.5, 171.0 MS m/z: 245 (M⁺ -15),203, 187

(Third step) Preparation ofmeso-2,4-O-isopropylidene-1,2,4,5-pentanetetraol (5)

A mixture ofmeso-1,5-diacetoxy-2,4-O-isopropylidene-2,4-dihydroxypentane (4) (15.2g, 0.6 mol) obtained at the second step with THF (250 ml) was dropwiseto a suspension of lithium aluminum hydride (4.6 g, 0.12 mol) and THF(125 ml) at 0° C. or lower, followed by agitating the mixture at roomtemperature for 2 hours, adding ethyl acetate (25 ml), water (25 ml) anda 2N aqueous solution of NaOH (5 ml) in this order, and agitating themixture at room temperature for 30 minutes.

The deposited crystals were filtered off, followed by washing thefiltration residue with THF (100 ml), combining the filtrate and THFused for the washing, concentrating the mixture under reduced pressureand subjecting the residue according to silica gel column chromatography(eluent, toluene: ethyl acetate (2:1) to obtain colorless, oilymeso-2,4-O-isopropylidene-1,2,4,5-pentanetetraol (5) (11.5 g, yield:quantitative).

¹ H-NMR (90 MHz, CDCl₃) δ(ppm): 1.3-1.59 (3H, m), 1.43 (3H, s), 1.47(3H, s), 3.40 (2H, brs), 3.62 (4H, m), 4.00-4.20 (4H, m)

(Fourth step) Preparation of (2R, 4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6)

A mixture of meso-2,4-O-isopropylidene-1,2,4,5-pentanetetraol (5) (8.2g, 4.6 mmol) obtained at the third step, vinyl acetate (100 ml) andLipase PS (made by Amano Pharmaceutical Co. Ltd. )(1 g) was agitated atroom temperature for one hour and 35 minutes, followed by filtering offthe Lipase PS, washing the filtration residue with ethyl acetate (10ml), combining the filtrate with ethyl acetate used for the washing andconcentrating the mixture under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent,toluene: ethyl acetate (2:1), Rf value: 2.3) to obtain colorless, oily(2R,4S)-erythro-1-acetyloxy-2,4-O-isorpopylidene-1,2,5-pentanetriol (6)(7.1 g, yield: 70%).

[α] D²⁷ +4.7° (2.56, CHCl₃) ¹ H-NMR (90 MHz, CDCl₃) δ(ppm): 1.3-1.55(2H, m), 1.43 (3H, s), 1.47 (3H, s), 2.08 (3H, s), 3. 40 (1H,brs), 3. 65(2H, m), 3. 97-4.20 (4H, m)

The optical purity of the thus obtained(2R,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6)was determined by deriving the (6) into MTPA(α-methoxy-α-(trifluoromethyl) phenylacetic acid) ester and subjectingit to 400 MHz-¹ H-NMR analysis as follows:

Namely, a mixture of(2R,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6)(115 mg, 0.53 mmol), R-α-methoxy-α-(trifluoromethyl)phenylacetic acidchloride (199 mg, 0.79 mmol) and pyridine (3 ml) was agitated at roomtemperature for 12 hours.

Water was added to the resulting material, followed by extracting withtoluene, washing the organic layer with a saturated aqueous solution ofsodium carbonate and then with water, drying over anhydrous magnesiumsulfate, filtering off the anhydrous magnesium sulfate, distilling offthe solvent under reduced pressure and subjecting the residue to silicagel column chromatography (eluent, toluene: ethyl acetate (3/1) toobtain a colorless, oily MTPA ester (250 mg). The peak of 3.56 ppmobserved by NMR analysis was a single peak; thus, (6) has been found tobe chemically pure.

¹ H-NMR (400 MHz, CDCl₃) δ(ppm): 1.29-1.32 (2H, m), 1.40 (3H, s), 1.42(3H, s), 3.56 (3H, s), 4.02-4.35 (6H, m), 7.40-7.57 (5H, m)

(Fifth step) Preparation of(2R,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-bromopentane(a compound of the formula (1) wherein R¹ represents bromine atom)

To a mixture of(2R,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol (6)(5.4 g, 0.025 mol) obtained at the fourth step with dichloromethane (100ml) were fed triphenylphosphine (7.8 g, 0.029 mol) and carbontetrabromide (12.3 g, 0.037 mol) in that order, followed by agitatingthe mixture at room temperature for one hour, adding a saturated aqueoussolution of sodium carbonate (2 ml), agitating for 30 minutes, anddrying over anhydrous magnesium sulfate.

The solids were filtered off, followed by washing the filtration residuewith dichloromethane (20 ml), concentrating the resultingdichloromethane under reduced pressure and subjecting the residue tosilica gel column chromatography (eluent, toluene: ethyl acetate (3:1))to obtain a colorless, oily(2R,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-bromopentane(a compound of the formula (1) wherein R¹ represents bromine atom) (5.4g, yield: 77%).

¹ H-NMR (90 MHz, CDCl₃) δ(ppm) :1.3-1.57 (2H, m), 1.44 (3H, s), 1.48(3H, s), 2.10 (3H, s), 3.45 (2H, q), 3.97-4.29 (4H, m)

(Sixth step) Preparation of(2S,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane(a compound of the formula (1) wherein R¹ represents cyano group)

A mixture of (2R,4S)-erythro-1-acetyloxy-2,4-O-propylidene-2,4-dihydroxy-5-bromopentane(a compound of the formula (1) wherein R¹ represents a bromine atom)(4.8 g, 0.017 mol) obtained at the fifth step, DMF (50 ml) and sodiumcyanide (1.7 g, 0.034 mol) was agitated at about 70° C. for one hour,followed by allowing the resulting material to cool, adding water (50ml) and extracting with ethyl acetate (50 ml).

The organic layer was twice washed with water (50 ml), followed bydrying over anhydrous magnesium sulfate, filtering off anhydrousmagnesium sulfate, concentrating ethyl acetate under reduced pressure,and subjecting the residue to silica gel column chromatography (eluent,toluene: ethyl acetate (5:1)), to obtain slightly yellow, oily (2S,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane(a compound of the formula (1) wherein R¹ represents cyano group) (2.1g, yield: 55%).

¹ H-NMR (400 MHz, CDCl₃) δ(ppm): 1.33-1.43 (2H, m), 1.42 (3H, s), 1.46(3H, s), 2.09 (3H, s), 2.50 (2H, q), 3.97.-4.25 (4H, m) ¹³ C-NMR (90MHz, CDCl₃) δ(ppm): 19.4, 20.7, 24.8, 29.5, 32.0, 64.6, 66.5, 66.6,99.3, 116.5, 170.6

EXAMPLE 2

(application example)

Preparation of(2R,4S)-erythro-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate (1-3)

To a mixture of(2S,4S)-erythro-1-acetyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane(a compound of the formula(1) wherein R¹ represents cyano group) (2.0 g,7.9 mmol) and dichloromethane (20 ml), a 1.0M solution of diisobutylaluminium hydride in toluene (24ml) was added dropwise at -70° C., andthe mixture was stirred for 20 min.

After adding methanol (5 ml), a saturated aqueous solution of ammoniumchloride (5 ml) and diethyl ether (5 ml), the resulting precipitate wasfiltered off, followed by concentrating the filtrate under reducedpressure to obtain (2R, 4S)-erythro-3,5-O-isopropylidene-3,5,6-trihydroxyhexanal (2.0 g).

A mixture of the aldehyde (2.0 g, 7.8 mmol) obtained above, DMF (100ml), methanol(1.6 ml) and pyridum dichromate was stirred for 40 min. Asaturated aqueous solution of sodium hydrogen carbonate was added underice cooling, followed by extracting the mixture with ethyl acetate,washing the organic layer with water and drying over anhydrous magnesiumsulfate.

Ethyl acetate was distilled off under reduced pressure, followed bysubjecting the residue to silica gel column chromatography (eluent:toluene-ethyl acetate (1:1)), to obtain colorless, oily (2R,4S)-erythro-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate (1-3) (1.57g, yield: 70%).

¹ H-NMR (400 MHz, CDCl₃) δ(ppm): 1.29-1.53 (2H,m), 1.39 (3H,s), 1.48(3H,s), 1.58 (3H, brs), 2.49 (2H,m), 3.56 (2H,m), 3.69 (3H,s), 4.02(1H,m), 4.34 (1H,m)

What we claim is:
 1. A process for producing an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentane,which process comprises reacting an ester containing a group R³ CO withmeso-1,2,4,5-pentanetetraol expressed by the formula ##STR38## in thepresence of a lipase which catalyzes an ester exchange reaction withprimary hydroxyl groups at a rate much greater than secondary alcoholgroups to prepare a meso-1,5-alkanoyloxy-2,4-dihydroxypentane expressedby the formula ##STR39## wherein R³ represents an alkyl group of 1 to 10carbon atoms; ketalizing the compound (3) to prepare ameso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentaneexpressed by the formula ##STR40## dealkanolizing the compound (4) toprepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed bythe formula ##STR41## reacting an ester containing a group R² CO with(5) in the presence of a lipase which catalyzes an ester exchangereaction with only one of the hydroxyl groups at the 1 and 5 positionsof compound (5) to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR42## wherein R² represents an alkyl group of 1 to 6carbon atoms, and halogenating compound (6) to prepare an opticallyactiveerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneexpressed by the formula ##STR43## wherein R¹ represents a halogen atomand R² represents an alkyl group of 1 to 10 carbon atoms.
 2. A processfor producing an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentane,which process comprises reacting an ester containing a group R³ CO withmeso-1,2,4,5-pentanetetraol expressed by the formula ##STR44## in thepresence of a lipase which catalyzes an ester exchange reaction withprimary hydroxyl groups at a rate much greater than secondary alcoholgroups to prepare a meso-1,5-alkanoyloxy-2,4-dihydroxypentane expressedby the formula ##STR45## wherein R³ represents an alkyl group of 1 to 10carbon atoms; ketalizing the compound (3) to prepare ameso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentaneexpressed by the formula ##STR46## dealkanolizing the compound (4) toprepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed bythe formula ##STR47## reacting an ester containing a group R² CO with(5) in the presence of a lipase which catalyzes an ester exchangereaction with only one of the hydroxyl groups at the 1 and 5 positionsof compound (5) to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR48## wherein R² represents an alkyl group of 1 to 6carbon atoms, halogenating compound (6) to prepare an optically activealkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneexpressed by the formula ##STR49## wherein R¹ represents a halogen atomand R² represents an alkyl group of 1 to 6 carbon atoms, and cyanizingcompound (1-1) to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentaneexpressed by the formula ##STR50## wherein R¹ represents a cyano groupand R² represents an alkyl group of 1 to 6 carbon atoms.
 3. A processfor producing an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR51## wherein R² represents an alkyl group of 1 to 6carbon atoms, which process comprises reacting an ester having an R² COgroup with meso-2,4-O-isopropylidene-1,2,4,5-pentanetetraol expressed bythe formula ##STR52## in the presence of a lipase which catalyzes anester exchange reaction with only one of the hydroxyl groups at the 1and 5 positions of compound (5).
 4. A process for producing ameso-1,5-dialkanoyloxy-2,4-dihydroxypentane expressed by the formula##STR53## wherein R³ represents an alkyl group of 1 to 10 carbon atoms,which process comprises reacting an ester having a R³ CO group withmeso-1,2,4,5-pentanetetraol expressed by the formula ##STR54## in thepresence of a lipase which catalyzes an ester exchange reaction withprimary hydroxyl groups at a rate much greater than secondary alcoholgroups.
 5. A process for producing an optically activeerythro-3,5-O-isopropylidene-3,5,6-trihydroxy-hexanoate, which processcomprises reacting an ester having an R³ CO group withmeso-1,2,4,5-pentanetetraol expressed by the formula ##STR55## in thepresence of a lipase which catalyzes an ester exchange reaction withprimary hydroxyl groups at a rate much greater than secondary alcoholgroups to prepare a meso-1,5-alkanoyloxy-2,4-dihydroxypentane expressedby the formula ##STR56## wherein r³ represents an alkyl group of 1 to 10carbon atoms; ketalizing the compound (3) to prepare ameso-1,5-dialkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxypentaneexpressed by the formula ##STR57## dealkanolizing the compound (4) toprepare meso-2,4-O-isopropylidene-1,2,4,5-pentane tetraol expressed bythe formula ##STR58## reacting an ester having an R₂ CO group with (5)in the presence of a lipase which catalyzes an ester exchange reactionwith only one of the hydroxyl groups at the 1 and 5 positions ofcompound (5) to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-1,2,5-pentanetriol expressedby the formula ##STR59## wherein R² represents an alkyl group of 1 to 6carbon atoms, halogenating compound (6) to prepare an optically activealkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-halogenopentaneexpressed by the formula ##STR60## wherein R¹ represents a halogen atomand R² represents an alkyl group of 1 to 6 carbon atoms, and cyanizingcompound (1-1) to prepare an optically activeerythro-1-alkanoyloxy-2,4-O-isopropylidene-2,4-dihydroxy-5-cyanopentaneexpressed by the formula ##STR61## wherein R¹ represents a cyano groupand R² represents an alkyl group of 1 to 6 carbon atoms, and convertingthe cyano group into an alkoxycarbonyl group, to prepare an opticallyactive erythro-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate expressedby the formula ##STR62## wherein R⁴ represents an alkyl group of 1 to 6carbon atoms.
 6. A process as claimed in claim 1 wherein ketalizing isconducted with acetone or 2,2-dimethoxypropane in the presence of anacid catalyst.
 7. A process as claimed in claim 2 wherein ketalizing isconducted with acetone or 2,2-dimethoxypropane in the presence of anacid catalyst.
 8. A process as claimed in claim 5 wherein ketalizing isconducted with acetone or 2,2-dimethoxypropane in the presence of anacid catalyst.
 9. A process as claimed in claim 1 wherein thedealkanolizing step is conducted under neutral or basic conditions. 10.A process as claimed in claim 2 wherein the dealkanolizing step isconducted under neutral or basic conditions.
 11. A process as claimed inclaim 5 wherein the dealkanolizing step is conducted under neutral orbasic conditions.
 12. A process as claimed in claim 1 wherein thedealkanolizing step is performed with a reducing agent.
 13. A process asclaimed in claim 2 wherein the dealkanolizing step is performed with areducing agent.
 14. A process as claimed in claim 5 wherein thedealkanolizing step is performed with a reducing agent.
 15. A process asclaimed in claim 1 wherein halogenation is performed with atetrahalomethane.
 16. A process as claimed in claim 2 whereinhalogenation is performed with a tetrahalomethane.
 17. A process asclaimed in claim 5 wherein halogenation is performed with atetrahalomethane.
 18. A process as claimed in claim 1 whereinhalogenation is performed with a halosuccinic acid.
 19. A process asclaimed in claim 2 wherein halogenation is performed with a halosuccinicacid.
 20. A process as claimed in claim 5 wherein halogenation isperformed with a halosuccinic acid.
 21. A process as claimed in claim 2wherein cyanizing is performed with a cyanide of sodium, potassium orcopper.
 22. A process as claimed in claim 5 wherein cyanizing isperformed with a cyanide of sodium, potassium or copper.
 23. A processas claimed in claim 5 wherein the step of converting comprises formingan aldehyde group from the cyano group with diisobutyl aluminum hydrideafter which the aldehyde is oxidized to a carboxyl group.